The lung is the major portal of entry for Mycobacterium tuberculosis, the cause of human tuberculosis. The lung is the site where immune responses to this bacterium are initiated, and where growth of the organism is controlled without complete eradication. Acquire immunity of T cells and macrophages controls infection in the majority of healthy individuals. The lung is not only the first site of infection, but also uniquely susceptible to M. tuberculosis. Mechanisms responsible for susceptibility of the lung to M. tuberculosis and the inability of acquired immunity to eradicate the bacteria are poorly understood. The murine model of aerogenic mycobacterial infection provides an excellent means to analyze the initiation and effector phases of acquired immunity to mycobacterial infection in the lung. This competitive renewal application for HL-55967 builds on the collaborative infrastructure developed during the last 4 years between Case Western Reserve University (CWRU) and Colorado State University (CSU) aimed at addressing immune mechanisms responsible for control of mycobacterial infection in the lung. The PI hypothesizes that mechanism(s) for the pulmonary susceptibility to M. Tuberculosis differ(s) according to stage and site of infection. Initially, M. Tuberculosis resists innate immune mechanisms in lung and uses alveolar and interstitial spaces as privileged sites. As acquired immunity develops, the ability of M. Tuberculosis to inhibit the function of antigen-processing cells becomes a dominant means to assure its survival within the lung. This hypothesis leads to the following specific aims: Aim1: To determine the mechanism(s) responsible for permissive mycobacterial growth in alveolar and interstitial lung macrophages and the role of chemokines and NK cells in control of mycobacterial growth during the innate phase of pulmonary M. Tuberculosis and M. bovis BCG infection. Aim2: To determine the ability of lung antigen presenting cells (alveolar macrophages, lung parenchymal macrophages and lung dendritic cells) to activate naive and memory T cells, and the mechanism(s) used by M. Tuberculosis to interfere with class II MHC antigen presenting cell function. Aim 3: To determine the ability of chemokines, CpG and cholera toxin to enhance innate and acquired immune defenses to M. bovis-BCG and M. Tuberculosis within lung.